N. Kurrle, P. Makowka, V. Schlipfenbacher, J. Kreitz, I. Alshamleh, M. Seibert, S. Kaleab, C. Aguilar Montero, S. Marin, D. Fuhrmann, F. Gatzke, C. Fernandes, N. Preman, B. Haeupl, S. Wolf, J. Jakob, A. Barati Sedeh, L. Fries, L. Boerner, H. Nuernberger, V. Stolp, R. Kumar, M. Thoelken, C. Muhs, C. Brandts, J. Martin, M. Lindner, T. Berg, J. J. Schuringa, D. S. Krause, B. Bruene, H. Bonig, S. Scheich, M. Cascante, T. Oellerich, H. Schwalbe, F. Schnuetgen, H. Serve
Acute myeloid leukemia (AML) cells exhibit pronounced metabolic plasticity, yet how amino acid supply is coordinated to sustain leukemic metabolism remains poorly understood. Here, we show that AML cells catabolize extracellular proteins as a major source of amino acids through lysosomal degradation of albumin. This proteocatabolic activity supports anabolic processes and mitochondrial energy production and establishes a regulated, high-throughput regime of primary nitrogen-containing metabolites (nitrogen regimen). Sustained proteocatabolism inevitably generates ammonia, and we find elevated ammonia concentrations in bone marrow plasma from newly diagnosed AML patients that decline with effective induction therapy. Using metabolomics, isotope tracing and targeted genetic and pharmacological manipulations, we identify glutamate-ammonia ligase (GS/GLUL) as a central enzyme that buffers proteocatabolism-derived ammonia by stabilizing intracellular nitrogen homeostasis. Loss of GS function limits sustainable nitrogen handling capacity, thereby impairing leukemic proliferation and delaying disease progression in vivo. Together, our findings define extracellular protein catabolism as a regulating nitrogen management strategy in AML and reveal GS as a capacity-defining vulnerability of proteocatabolic growth.